Paolini, E.; Longo, M.; Meroni, M.; Podini, P.; Maggioni, M.; Quattrini, A.; Fracanzani, A. L.; Dongiovanni, P.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has been an increasing worldwide charge on healthcare owing to scant management and prevention. MASLD pathogenesis is fashioned by environmental and genetic factors and featured by the loss of mitochondrial dynamics. Recently, we demonstrated that the co-presence of loss-of-function polymorphisms in patatin-like phospholipase domain-containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound o-acyltransferase domain-containing 7 (MBOAT7) hugely predisposed to MASLD progression, revealing first their involvement in mitochondrial maladaptation in a genetics-based knock-out in vitro model. To deepen the genetics-mitochondria duo, in this work we generated wild type overexpressed cell lines in which TM6SF2 and/or MBOAT7 deleted proteins were functionally restored, resulting in physiological spaghetti-shaped mitochondria characterized by improved OXPHOS capacity. To translate our in vitro findings into a clinical perspective, we compared hepatic and peripheral bioenergetic profiles in MASLD patients carrying PNPLA3, MBOAT7 and/or TM6SF2 variations. The serum mitochondrial respirometry lowered mainly in 3 at-risk variants carriers completely reflecting the hepatic one, thus recommending the applicability of mitochondrial circulating non-invasive biomarkers to prognose genetic MASLD severity.